Evaluation and Predictive Factors of Complete Response in Rectal Cancer after Neoadjuvant Chemoradiation Therapy
Abstract
:1. Introduction
2. Tumor Reaction to the NAT—Defining the Terms
3. Complete Tumor Response after NAT
3.1. Clinical Complete Response (cCR)
- the absence of any irregularities or a palpable tumor on digital rectal examination,
- no visible lesion on endoscopy with the exception of a flat scar, telangiectasia, or whitening of the mucosa;
- 3.
- absence of any residual tumor in the primary site and draining lymph nodes on imaging with magnetic resonance imaging (MRI) or endorectal ultrasound (ERUS),
- 4.
- negative biopsies from the scar,
- 5.
- an initially raised CEA level that returns to normal (<5 ng/mL) [2].
3.2. Pathological Complete Response (pCR)
4. Diagnostic Accuracy of CR
4.1. Reassessment/Response Assessment after NAT
4.2. Digital Rectal Examination (DRE)
4.3. Proctoscopy/Endoscopy
4.4. Biopsy
4.5. Magnetic Resonance Imaging (MRI)
4.6. Computed Tomography (CT)
4.7. Positron Emission Tomography/Computed Tomography (PET/CT)
4.8. Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI)
4.9. Endorectal Ultrasound (ERUS)
5. Therapy-Related Predictive Factors of CR
5.1. Modalities of Neoadjuvant Radiation Therapy
5.1.1. External-Beam Radiation Therapy (EBRT)
- SCPRT also known as the 5 × 5 Gray (Gy) regimen, offers 5 daily doses of 5 Gy (total of 25 Gy) and is usually followed by radical resection within one week of completing RT (<10 days from the first radiation fraction). SCPRT with delayed surgery is also a useful alternative to conventional SCPRT with immediate surgery offering similar oncological outcomes and lower postoperative complications [3];
- LCPRT regimens deliver daily doses of RT in significantly smaller fractions (about 1.8–2 Gy) over a longer period of 25 days to 28 days. The total RT dose delivered by this regimen is 45 Gy to 54 Gy and seems to be biologically equivalent to the 25 Gy short-course regimen [59].
5.1.2. High Dose Endorectal Brachytherapy (HDRBT)
5.1.3. Contact X-ray Brachytherapy (Papillon)
5.2. Modalities of Neoadjuvant Chemoradiation Therapy (nCRT)
5.3. Neoadjuvant ChT
5.4. Interval to the Surgery
6. Host Related Predictive Factors of CR
6.1. Clinical Parameters
6.2. Genetic Predisposition
7. Tumor Related Predictive Factors of CR
7.1. Clinical Parameters
7.2. Morphological and Immunohistochemical Parameters
- the Dworak classification,
- the ypTNM staging, i.e., the post-surgical pathologic examination,
- the NAR score (Valentini V et al. in 2011 developed a nomogram for predicting local recurrence, distant metastases, and OS for patients with LARC. The nomogram for OS takes into consideration patient age, gender, the clinical tumor (cT) stage, pathologic tumor (pT) stage, pathologic nodal (pN) stage, the dose of radiotherapy, adjuvant chemotherapy administration and surgery type–abdominoperineal resection vs. low anterior resection) [107,108,109].
7.3. Tissue-Based Tumor Molecular Biomarkers
7.3.1. DNA Mutation and DNA Methylation
7.3.2. Gene Expression Profiles
7.3.3. MicroRNA (miRNA)
7.4. Blood-Based Tumor Molecular Biomarkers
7.4.1. Protein and Metabolites
7.4.2. MicroRNA (miRNA)
7.4.3. Circulating Tumor Cells (CTCs)
7.4.4. Circulating Cell-Free Nucleic Acids
7.4.5. Host Immune Response
8. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Grade | Response Criteria |
---|---|
Complete response (CR) | The disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to <10 mm. |
Partial response (PR) | At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Progressive disease (PD) | At least 20% increase in the sum of diameters of target lesions, the appearance of one or more new lesions is also considered progression. |
Stable disease (SD) | Neither sufficient shrinkage to qualify for a partial response nor sufficient increase to qualify for progressive disease. |
TRG | Mandard | Dworak | Ryan/AJCC | MSKCC |
---|---|---|---|---|
TRG 0 | - | no response | CR, no viable cancer cells | - |
TRG 1 | complete regression, no viable cancer cells, fibrosis extending through the different layers of the wall | minimal response (dominant tumor mass with obvious fibrosis, vasculopathy); fibrosis <25% of tumor mass | near-CR, single cells or rare small group of cancer cells | 100% tumor response |
TRG 2 | rare residual cancer cells scattered through the fibrosis | moderate response (dominant fibrotic changes with a few easy-to-find tumor cells in groups); fibrosis 25–50% of tumor mass | partial response, residual cancer with evident tumor regression but more than single cells or rare small group of cancer cells | 86–99% tumor response |
TRG 3 | increased number of residual cancer cells, fibrosis predominates | near CR (few microscopically difficult-to-find tumor cells in fibrotic tissue with or without mucous substance); fibrosis > 50% of tumor mass | poor or no response, extensive residual cancer with no evident tumor regression | ≤85% tumor response |
TRG 4 | residual cancer outgrowing fibrosis | CR (no tumor cells, only fibrotic mass or acellular mucin pools) | - | - |
TRG 5 | absence of regressive changes | - | - | - |
Grade | Response | mrTRG (2012) | MERCURY (2012) | MERCURY (2016) | ESGAR (2016) |
---|---|---|---|---|---|
mrTRG 1 | Complete | No evidence of treated tumor. Thin fibrosis, low-density signal on T2-weighted images with no evidence of intermediate signal intensity at the site of the treated disease. | No evidence of tumor signal intensity or fibrosis only | Linear/crescentic 1–2 mm scar in mucosa or submucosa only | Completely normalized rectal wall |
mrTRG 2 | Good | Dense fibrosis (>75%); no obvious residual tumor, signifying minimal residual disease, or no tumor. Dense fibrosis with no macroscopic evidence of intermediate T2 signal intensity. | Dense hypointense fibrosis with minimal residual tumor | No obvious residual tumor, signifying minimal residual disease or no tumor | Fibrotic wall thickening without clear mass |
mrTRG 3 | Moderate | >50% fibrosis or mucin and visible intermediate signal intensity. Predominating low signal fibrosis with macroscopic scattered or local intermediate signal intensity. | >50% fibrosis/mucin and visible tumor with intermediate signal intensity | >50% fibrosis/mucin and visible tumor with intermediate signal intensity | Residual mass (and/or focal high signal intensity on diffusion-weighted imaging) |
mrTRG 4 | Slight | little areas of fibrosis or mucin, but mostly tumor. Predominating intermediate T2-weighted signal with minimal or no fibrosis present. | Little areas of fibrosis/mucin, but mostly tumor | Little areas of fibrosis/mucin, but mostly tumor | |
mrTRG 5 | No response | Intermediate signal intensity; same appearance as that of the original tumor. Predominating intermediate T2-weighted signal with minimal or no fibrosis present. | Intermediate signal intensity, same appearances as original tumor/tumor regrowth | Intermediate signal intensity, same appearances as original tumor/tumor regrowth |
Upregulated miRNA | Downregulated miRNA | ||
---|---|---|---|
miR-137 | miR-143 | miR-923 | miR-720 |
miR-125 | miR-194 | miR-486-5p | miR-215 |
miR-1183 | miR-866-3p | miR-34b | miR-190b |
miR-483-5p | miR-379 | miR-1274b | miR-29b-2 |
miR-125a-3p | miR-154 | miR-450a | miR-590-5p |
miR-1224-5p | miR-1542-5p | miR-450b-5p | miR-153 |
miR-622 | miR-363 | miR-99a | miR-519c-3p |
miR-196b | miR-1290 | miR-519b-3p | miR-561 |
miR-223 | miR-188-5p | miR-1233 | miR-30b |
miR-494 | miR-1471 | miR-650 | miR-145 |
miR-513a-5p | miR-1909 | miR-1243 | miR-148a |
miR-513b | miR-21-5p | miR-125b | miR-375 |
miR-31 | miR-671-5p | miR-345 | miR-519b |
miR-451 | miR-630 | let-7e | miR-1123 |
miR-335 | miR-765 | let-7f | |
miR-144 | miR-193a-5p | miR-135b | |
miR-18a | miR-1290-3p | miR-16 | |
miR-487a-3p | miR-382 | miR-21 | |
miR-1246 | miR-19-3p | miR-200c |
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Kokaine, L.; Gardovskis, A.; Gardovskis, J. Evaluation and Predictive Factors of Complete Response in Rectal Cancer after Neoadjuvant Chemoradiation Therapy. Medicina 2021, 57, 1044. https://doi.org/10.3390/medicina57101044
Kokaine L, Gardovskis A, Gardovskis J. Evaluation and Predictive Factors of Complete Response in Rectal Cancer after Neoadjuvant Chemoradiation Therapy. Medicina. 2021; 57(10):1044. https://doi.org/10.3390/medicina57101044
Chicago/Turabian StyleKokaine, Linda, Andris Gardovskis, and Jānis Gardovskis. 2021. "Evaluation and Predictive Factors of Complete Response in Rectal Cancer after Neoadjuvant Chemoradiation Therapy" Medicina 57, no. 10: 1044. https://doi.org/10.3390/medicina57101044